This Physician Scientist Award proposal outlines a five year plan aimed at providing the rigorous and thorough scientific knowledge and training necessary for an active investigative career in academic medicine. Phase I focuses heavily on a didactic component of graduate level course work in molecular biology and developmental biology at Harvard University and Massachusetts Institute of Technology, attendance at seminars at Harvard/Massachusetts Institute of Technology/Massachusetts General Hospital, and the acquisition of basic skills in Dr. Mark Fishman's laboratory at the Howard Hughes Medical Institute. The laboratory work will involve initially the cloning and sequencing of the human growth-associated protein (GAP-43) gene. The GAP-43 gene is known to be important in growth and remodeling of neurites during development, but its persistence in the adult CNS, as demonstrated in Dr. Fishman's laboratory, suggests that GAP-43 may also be critical for preserving neuronal plasticity, and involved in synapse remodelling and perhaps learning and memory in the fully mature nervous system. The rat GAP-43 gene was cloned recently in Dr. Fishman's laboratory, and extensive work is currently underway in his laboratory to understand its regulation at the levels of transcription and translation. In addition to cloning the human GAP-43 gene, toward the latter half of Phase I the candidate will begin to examine the role of GAP-43 in neuronal plasticity in the mature and aging peripheral and central nervous system using models of sprouting, repair, and regeneration in experimental animals. During Phase II, the theoretic framework and techniques learned in Phase I will be utilized to continue studying molecular aspects of neuronal plasticity, regeneration, and repair in experimental animals, and to investigate molecular aspects of human neurodegenerative diseases which have features suggestive or indicative of aberrant neuronal plasticity, principally Alzheimer's disease. The Phase I environment will provide the opportunity to learn the techniques of cloning, hybridization analyses, protein chemistry, immunocytochemistry, and in situ hybridization in the context of biological systems relevant to study of neuronal plasticity. Progress during Phase I will be evaluated by a research advisory committee with a commitment to the thorough scientific education of physicians. A long-term objective of this work will be to apply insights gained at the molecular level toward developing effective treatment or preventive measures against Alzheimer's Disease.